The primary function of this application is to engineer functional polymeric micelles which target solid tumors in acidic extracellular fluid and utilize acidic endosome to treat sensitive and multidrug resistant (MDR) tumors. It is estimated that more than 80% of measured tumor extracellular pH (pile) are below 7.2. For intracellular pH of tumor cells, parenteral drug sensitive cells are characterized to have rather acidic, diffuse cytosolic pH profile; however MDR cells develop more acidic organelles (recycling endosome, lysosome and trans-Golgi network) than cytosol and necleoplasmic pH. Our preliminary results demonstrate that the polymeric micelles composed of poly(L-histidine)/PEG and PLLA/PEG enhanced the release rate of a loaded model anticancer drug (doxorubicin (DOX) in this study) by physical destabilization of the micelle core at pile, resulting in higher cytotoxicity at lower pH. In addition, the micelles, conjugated with folate and destabilized at pH 6.8, showed great efficacy for sensitive and MDR cells after folate receptor-mediated endocytosis. Therefore it is hypothesized that triggered release of DOX from the intelligent polymeric micelles at tumor pile is a more effective modality in cancer chemotherapy, proving higher local concentration at tumor sites (targeted high-dose chemotherapy), while a minimal release during circulation occurs. The micelle destabilization may help further accumulation of the micelles by reducing the physical barriers in the interstitial space. Another hypothesis is that after receptor-mediated endocytosis, simultaneous triggered release in early endosomes (approximately pH 6) and endosomal disruption will provide high concentrations of the drug in cytosol and nucleus. This will be effective not only for sensitive and but for MDR cells where the drug diffusivity the plasma membrane is compromised and the pumping activities of Pgp and MRP. This approach will be especially useful for weakly basic drugs of which partitioning between cytosol and subcellular organelles is greatly influenced by pH gradient (sequestration). The goals of this research are 1) to design biodegradable polymers sensitive to tumor acidity and to engineer polymeric micelles with or without targeting moiety that can truly recognize tumor pile or endosomal pH for triggered release, while keeping a minimal release rate during circulation and 2) to assess the proposed hypotheses for improved chemotherapy.